Cyclooxygenase (COX) inhibitors have an established place in the treatment of thrombotic and[unreadable] inflammatory diseases. Although randomized clinical trials have established that low dose aspirin is[unreadable] efficacious in the secondary prevention of stroke and myocardial infarction, it has been suggested[unreadable] that a syndrome of "aspirin resistance" constrains its efficacy in up to a third of aspirin users. We[unreadable] propose to determine the stability, specificity and consequent incidence of the "aspirin resistant"[unreadable] phenotype, to compare the ability of aspirin to prevent transient haemostatic activation by bacterial[unreadable] lipopolysaccharide (IPS) in "resistant" and "responsive" individuals, to define novel lipidomic and[unreadable] proteomic signatures of aspirin resistance and to relate conventional and novel biomarkers of this[unreadable] phenotype to a surrogate of clinical outcome- progression of atherosclerotic plaque burden. Specific[unreadable] Aim 1 addresses the incidence of a stable and specific phenotype of "aspirin resistance" in healthy[unreadable] volunteers given aspirin by measuring platelet aggregation and both ex vivo and in vivo indices of[unreadable] platelet prostaglandin production. Specific Aim 2 will determine the impact of a resistant phenotype[unreadable] on inhibition of evoked haemostatic activation by aspirin. The impact of low dose aspirin on the[unreadable] prevention of hemostatic activation by lipopolysaccharide in "resistant" and "responsive" volunteers[unreadable] will be studied to determine the impact of combined inhibition of COX-1 and COX-2 on haemostatic[unreadable] activation by IPS in these subsets, to identify novel proteomic and lipidomic signatures which[unreadable] identify individuals as "aspirin resistant", and to identify genetic variants of COX-1 which correspond[unreadable] to the resistant phenotype. Specific Aim 3 will relate prospectively individual biomarkers of the[unreadable] stable aspirin-resistant phenotype to carotid and coronary artery plaque progression, relate novel[unreadable] proteomic and lipidomic biomarkers of resistance to this clinical surrogate of cardiovascular disease[unreadable] in patients treated with aspirin, and initiate assessment of the correlation of genetic covariants of[unreadable] resistance with cardiovascular events in patients treated with aspirin.